[Translation] A Phase I clinical study to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of GT1708F in the treatment of patients with malignant hematological diseases

主要目的：评价不同剂量的GT1708F在恶性血液病患者中的安全性和耐受性，观察可能出现的剂量限制性毒性（DLT）和最大耐受剂量（MTD）； I期研究次要目的：评价GT1708F单次和连续多次给药在恶性血液病患者中的药代动力学（PK）特征；评价单药GT1708F在恶性血液病患者中的初步有效性。

[Translation]

Primary purpose: To evaluate the safety and tolerability of different doses of GT1708F in patients with hematological malignancies, and to observe possible dose-limiting toxicity (DLT) and maximum tolerated dose (MTD); Phase I study Secondary purpose: To evaluate the pharmacokinetic (PK) characteristics of single and continuous multiple administrations of GT1708F in patients with hematological malignancies; To evaluate the preliminary efficacy of single-agent GT1708F in patients with hematological malignancies.

Start Date23 Nov 2020

Sponsor / Collaborator

Suzhou Kintor Pharmaceuticals, Inc.

100 Clinical Results associated with SMO x SHH

100 Translational Medicine associated with SMO x SHH

0 Patents (Medical) associated with SMO x SHH

616

Literatures (Medical) associated with SMO x SHH

01 Jan 2025·Life Sciences

Halcinonide activates smoothened to ameliorate ischemic stroke injury

Article

Author: Kang, Jia ; Liu, Jingjing ; Liu, Xiaohua ; Chen, Xinping ; Meng, Xinrui ; Zhou, Jing ; Hu, Zhuozhou ; Zhao, Wenyang ; Zhang, Yixuan ; Li, Xiangxiang ; Han, Liang ; Gao, Xiaoshan ; Gu, Youquan

OBJECTIVESThe Shh pathway may shed new light on developing new cell death inhibitors for the therapy of ischemic stroke. We aimed to examine whether the Shh co-reporter SMO or its agonist halcinonide can upregulate Bcl-2 to suppress neuronal cell death, ultimately improving behavioral deficits and reducing cerebral infarction in an ischemic stroke model.METHODSHalcinonide or genetic manipulation of SMO was conducted in PC12 cells to examine their impacts on oxidative or OGD/R stress, and the chemical, along with AAV-SMO or AAV-EGFP were tested in MCAO rats to investigate their potential protective effects against neuronal damages due to cerebral I/R injury. The amounts or activities of L-LA, LDH, ROS, MDA, SOD, MPO, GSSG, and GSH were detected using the corresponding biochemical kits. The levels of TNF-α and IL-6 were analyzed by ELISA.RESULTSThe results show that halcinonide alleviated neurological score and cerebral infarction, and the abnormal changes in L-LA, LDH, MDA, SOD, MPO, GSH, GSSG, TNF-α, and IL-6 were also reversed in MCAO rats. Through expression or knockout of SMO, we discovered that SMO worked similarly to halcinonide, protecting neuronal cells from oxidative or OGD/R stress, and AAV-SMO prevented cerebral damages of MCAO rats caused by ischemia and reperfusion. Halcinonide inhibited Bcl-2/Bax-mediated apoptosis, at least partially by promoting the Shh signaling pathway through enhancing SMO expression in vivo and in vitro.CONCLUSIONThis study identified a new target and a candidate chemical for therapy of ischemic stroke, hopefully reducing its morbidity and mortality.

01 Dec 2024·Molecular Biology Reports

Effects of mesenchymal stem cells versus curcumin on sonic hedgehog signaling in experimental model of Hepatocellular Carcinoma

Article

Author: Fouad, Hanan ; Sedeak, Ahmed Yahia ; Reyad, Hoda Ramadan ; Faruk, Eman ; Rateb, Enas Ezzat ; Abdel-Tawab, Marwa Sayed ; Doudar, Noha A

BACKGROUNDSonic Hedgehog (SHH) is a fundamental signaling pathway that controls tissue reconstruction, stem cell biology, and differentiation and has a role in gut tissue homeostasis and development. Dysregulation of SHH leads to the development of HCC.METHODS, AND RESULTSThe present study was conducted to compare the effects of mesenchymal stem cells (MSCs) and curcumin on SHH molecular targets in an experimental model of HCC in rats. One hundred rats were divided equally into the following groups: control group, HCC group, HCC group received MSCs, HCC group received curcumin, and HCC group received MSCs and curcumin. Histopathological examinations were performed, and gene expression of SHH signaling target genes (SHH, PTCH1, SMOH, and GLI1) was assessed by real-time PCR in rat liver tissue. Results showed that SHH target genes were significantly upregulated in HCC-untreated rat groups and in MSC-treated groups, with no significant difference between them. Administration of curcumin with or without combined administration of MSCs led to a significant down-regulation of SHH target genes, with no significant differences between both groups. As regards the histopathological examination of liver tissues, both curcumin and MSCs, either through separate use or their combined use, led to a significant restoration of normal liver pathology.CONCLUSIONSIn conclusion, SHH signaling is upregulated in the HCC experimental model. MSCs do not inhibit the upregulated SHH target genes in HCC. Curcumin use with or without MSCs administration led to a significant down-regulation of SHH signaling in HCC and a significant restoration of normal liver pathology.

01 Nov 2024·Biochemistry (Moscow)

Purmorphamine Alters Anxiety-Like Behavior and Expression of Hedgehog Cascade Components in Rat Brain after Alcohol Withdrawal

Article

Author: Kvichansky, Aleksei A ; Gulyaeva, Natalia V ; Shirobokova, Nataliya I ; Peregud, Danil I ; Stepanichev, Mikhail Yu

Disturbances in the Hedgehog (Hh) signaling play an important role in dysmorphogenesis of bone tissue and central nervous system during prenatal alcohol exposure, which underlies development of fetal alcohol syndrome. The involvement of Hh proteins in the mechanisms of alcohol intake in adults remains obscure. We investigated the role of the Hh cascade in voluntary ethanol drinking and development of anxiety-like behavior (ALB) during early abstinence and assessed changes in the expression of Hh pathway components in different brain regions of male Wistar rats in a model of voluntary alcohol drinking using the intermittent access to 20% ethanol in a two-bottle choice procedure. Purmorphamine (Hh cascade activator and Smoothened receptor agonist) was administered intraperitoneally at a dose of 5 mg/kg body weight prior to 16-20 sessions of alcohol access. Purmorphamine had no effect on the ethanol preference; however, rats exposed to ethanol and receiving purmorphamine demonstrated changes in the ALB during the early abstinence period. Alcohol drinking affected the content of the Sonic hedgehog (Shh) and Patched mRNAs only in the amygdala. In rats exposed to ethanol and receiving purmorphamine, the level of Shh mRNA in the amygdala correlated negatively with the time spent in the open arms of the elevated plus maze. Therefore, we demonstrated for the first time that alterations in the Hh cascade induced by administration of purmorphamine did not affect alcohol preference in voluntary alcohol drinking. It was suggested that Hh cascade is involved in the development of anxiety after alcohol withdrawal through specific changes in the Hh cascade components in the amygdala.

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